A PHASE 1 STUDY OF PS-341 IN COMBINATION WITH 5-FU/LV IN SOLID TUMORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一项第一阶段的研究，目标如下：确定PS-341在转移性实体瘤患者中静脉注射时的剂量限制毒性（DLT）和最大耐受剂量（MTD），每周两次，联合每周5-FU和LV。2. 通过检测静脉注射PS-341联合每周5-FU和LV治疗患者血液中20S蛋白酶体和NFkB的抑制程度，评价PS-341的药效学。二级:1。目的：确定静脉注射PS-341治疗患者的客观肿瘤反应。2. 探讨20S蛋白酶体和NFkB抑制与临床毒性的关系。3. 基于PS-341的作用机制，获得PS-341和5-FU、LV应答的分子相关基因，包括参与凋亡、细胞周期控制、转录调控和粘附/血管生成的基因。4. 观察5-FU与PS-341合用时的药代动力学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a Phase I Study with the following objectives: Primary: 1. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of PS-341 when administered as an intravenous bolus twice weekly combined with weekly 5-FU and LV in patients with metastatic solid tumors. 2. To evaluate the pharmacodynamics of PS-341 by determining the 20S proteasome and NFkB inhibition in blood of patients treated with intravenous PS-341 combined with weekly 5-FU and LV. Secondary: 1. To identify any objective tumor response in patients treated with intravenous PS-341. 2. To evaluate the relationship between inhibition of the 20S proteasome and NFkB and clinical toxicity. 3. To obtain preliminary data on molecular correlates of response to PS-341 and 5-FU and LV including genes involved in aptosis, cell cycle control, transcriptional regulation and adhesion/angiogenesis based on the mechanisms of PS-341. 4. To examine the pharmacokinetics of 5-FU when co-administered with PS-341.